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01. What is the significance of determining the particle size of the drug substance stability?

Answer: The particle size measurement of stability is generally in the IND stage, which is to guide the determination or optimization of the formulation process.

02. How to design stable microbial inspection sites?

A: The frequency of microbiological testing is once a year. 0:00, December, 24, 36. For accelerated testing, it is also tested at the last point (June).

03. How long must the test be completed after the stability sample is taken out?

A: There is no clear rule on how long it will take to complete the regulations. The stability point within six months is usually tested within 15 days, and the stability point after six months is completed within one month. This refers to calendar days, not working days.

04. Significant changes in dissolution rate in stability, including the dissolution rate should be 5% different from the initial value or just meet the regulations?

Answer: Not included, it can meet the regulations. A 5% difference from the initial value applies only to the content.

05. When the stability box sends an alarm by SMS, does it need to record the temperature and humidity before and after the change, and explain the reason? What if I call the police in the middle of the night?

Answer: If possible, the management of the stability box is best to be an automatic monitoring system, so that the data is available at any time, even if it is an alarm in the middle of the night. If you can get a call, it should be an automatic system. In this way, it is necessary to print out the temperature and humidity records of the corresponding time period and mark the abnormality. Generally, the abnormality will last for a period of time. At this time, the cause should be found out and explained in the record. If it is only an exception at a certain point in time, it also needs to be marked, but it does not need to be processed. At this time, it may be caused by a change. Short-term changes have no effect on the sample.

06. The original research instructions often indicate that the storage is below 30°C. Does the long-term stability of self-made products need to be done at 30°C, but not at 25°C?

A: The choice of the long-term stability conditions of the original research depends on where the product is to be marketed and which climatic zone it conforms to. For example, the long-term conditions of the climate zone Zone IVa in ICH Q1F are 30℃-65℃, the label should be 30℃. But for use in China, if you plan to store it at room temperature, the long-term condition is 25°C-60°C.

07. If the stability box needs to perform periodic PQ during the stability investigation, and the samples inside need to be transferred during the no-load calibration, in this case, is it necessary to evaluate the impact of the transfer step on the samples?

A: Change control needs to be written when the sample is transferred, so an evaluation is required, and the content of the evaluation is included in the change control report.

08. In the stability test, is the dissolution curve required at each time point? All four conditions to be done? Or can the dissolution profile of standard conditions be done? Is the dissolution curve not the dissolution rate in the stability test?

A: The stability test and dissolution test can be measured at a single point, and the IND will not be so strict. However, it is still recommended to measure each point, so that you can see the profile.

09. When doing the stability test of API, the conditions in the IF file are often referred to. Accelerated 40℃ and long-term 25℃, the quality does not change. Can the storage conditions in the standard be reserved at room temperature?

A: It can be stored at room temperature.

10. If it is transferred to another stability box under the same storage conditions, and the transfer process takes a short time, can it be assessed that the intermittent time will not affect the product quality? How to control this time?

Answer: It can be evaluated. Generally, the deviation within 24 hours will not affect the sample. This is mentioned in ICH. This is also the purpose of the influencing factor experiment, which is to see the impact of the short-term out-of-range on the sample. However, it is still necessary to ensure that the transfer is completed as soon as possible, the shorter the time, the less likely to be questioned.

11. During the stability inspection, the samples are generally kept according to the commercially available packaging. If it is one plate per box, which is limited by the space of the stability box, can two plates and one box be placed?

Answer: No. Two plates and one box are not commercially available packaging. If the reserved samples are used for testing in the future, and the packaging is different, it is difficult to evaluate the results.

12. After the packaging of the raw materials is packaged, for the convenience of sampling, the samples at the same time point are placed in a cardboard barrel for stability inspection. Is this cardboard barrel allowed to be used?

A: It can be put in a cardboard bucket.

13. Can the no-load temperature distribution verification be done for the first time, and only load during periodic verification?

A: Just do the load.

14. If there is a one-day failure of the constant temperature and humidity box during the stability inspection period, does the time for sample removal need to be postponed for one day?

A: In this case an Incident Report or Deviation Report is to be written to assess how much impact the day's failure has had on the sample. If there is no impact on the assessment, there is no need to postpone it, and normal sampling can be done. If the assessment has an impact or cannot be assessed, it can be postponed by one day. The key is that the report must be written. In fact, the sampling of stability points has a window. Generally, the points three months ago (including 3 months) are not more than one day in advance and no more than 3 days later. The point after 4 months can be advanced or delayed by 5 days, depending on how it is defined in the SOP. The requirements of this different company will have subtle differences.

15. Whether the inspection month is calculated according to 30 days, or according to one month, such as February 28, how to deal with it?

A: This is a special case. This has happened to me in projects I've been through. In order to facilitate the management of the samples, we took the samples according to the date of the corresponding February. For example, if the stake is set out on August 30, then February 28 will be the sampling point for 6 months. But I personally recommend taking this into account when staking, and try to avoid the sampling point of the first three months in February. After 3 months, it will not have much impact (you can refer to question 14).

16. An OOS survey takes several months. How can the stability data of this point be reflected? And if the OOS investigation is not over yet, what if the next time has come?

A: One stability point is often to measure multiple items, so in addition to the OOS data, other data are reported normally. The OOS data were laboratory investigated until the root cause was found. If it is a laboratory error, report the data from the retest, even if it has been several months since the retest. In the case of confirmed OOS results, both the original and retest results are reported. If the OOS investigation has not ended and the next time point has come, it is still normal sampling and normal testing.

17. New inspection items are added to the stability inspection process. How to determine the 0-day data?

Answer: If it is assessed that the previous stability point does not need to add new inspection items, then the added point is the starting point. This should be clearly stated in the stability data evaluation report. If it is estimated that the previous point needs to be redone, then the starting point of redoing is 0 point data. Also make it clear in the stability report.

18. If crystals are precipitated on the surface of the accelerated June tablet in both the reference preparation and the self-made tablet, and the material is not conserved, it is later found that the precipitated crystals are known degradation impurities and can be sublimated. If it cannot be captured, is it that as long as the phenomenon is consistent with the reference, there is no need to continue the research?

A: The comparison of phenomena alone is not enough to indicate whether to continue research. Only data is the most convincing. For example, is the law of non-conservation the same? Is the content the same?

19. Do microorganisms need to be tested at the accelerated 6-month point?

A: It needs to be tested, and the accelerated test for 6 months is the last point.

20. Under what circumstances will new inspection items be added during the stability inspection process? How to determine the 0-day data of the added inspection items?

Answer: Sometimes it is found in the stability inspection that new inspection items need to be added to fully reflect the stability of the product. For example, it is found that the indicators such as moisture, friability, and dissolution curve are very important in the stability of the tablet. Therefore, the above indicators are added, then The original stability study data is still very interesting, reflecting the stability of the product in the previous stage. In the follow-up stability inspection, all items should be inspected. This problem reflects that when designing the stability plan, the characteristics of the dosage form and the inspection indicators in the stability plan of the drug at home and abroad should be selected, and the design should be fully and reasonably designed to reduce the occurrence of subsequent addition of new inspection items. As for the 0-day data, if it is estimated that the previous stability point does not need to add new inspection items, the added point is the starting point. This should be clearly stated in the stability data evaluation report. If it is estimated that the previous point needs to be redone, then the starting point of redoing is 0 point data. Also make it clear in the stability report.

21. Regarding the stability of the commercially available packaging, is it enough that the inner packaging is the same? Why should the packaging of the small box be the same?

A: According to the ICH guidelines, the packaging during the stability study should be the same or similar to the packaging in the market. In the same way, drugs are related to the safety of the human body. If you cannot evaluate the risk well, it is recommended to use the same or similar packaging. The data is the most favorable support. YENHE Scientific Instrument (Shanghai) Co., Ltd. specializes in the production of drug stability test chambers to solve any troubles you encounter during the stability inspection process. Welcome to inquire~